(a) Field of the Invention
This invention relates to thiazolylpyridinones, their preparation and their use as cardiotonics.
(b) Description of the Prior Art
Lesher and Opalka [U.S. Pat. Nos. 4,004,012, issued Jan. 18, 1977, and 4,072,746, issued Feb. 7, 1978] show as cardiotonic agents 3-amino(or cyano)-5-(pyridinyl)-2(1H)-pyridinones. A preferred embodiment of these compounds is 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, now generically known as amrinone and alternatively named 5-amino-[3,4'-bipyridin]-6(1H)-one. Various methods are shown for preparing the 3-cyano-5-(pyridinyl)-2(1H)-pyridinones, alternatively named 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitriles, for example, by reacting .alpha.-(pyridinyl)-.beta.-(dialkylamino)acrolein with .alpha.-cyanoacetamide and the conversion of said substituted-nicotinonitriles to the corresponding substituted-nicotinamides and substituted-nicotinic acids. U.S. Pat. No. 4,072,746 also shows, inter alia, 3-Q-5-(pyridinyl)-2(1H)-pyridinones where Q is hydrogen by decarboxylating the corresponding compound where Q is carboxy. The disclosure of U.S. Pat. No. 4,072,746 also is shown in Lesher and Opalka U.S. Pat. Nos. 4,107,315, 4,137,233, 4,199,586 and 4,225,715.
Lesher, Opalka and Page U.S. Pat. No. 4,276,293, issued June 30, 1981, shows inter alia 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles by reacting a 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone with .alpha.-cyanoacetamide and the conversion, by hydrolysis and decarboxylation, of said nicotinonitriles to the corresponding 6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones.
Lesher and Philion U.S. Pat. No. 4,313,951, issued Feb. 2, 1982 from application Ser. No. 198,461, filed Oct. 20, 1980 as a continuation-in-part of application Ser. No. 97,504, filed Nov. 26, 1979 and now abandoned, discloses and claims as cardiotonics, inter alia, 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)-nicotinonitriles and their preparation, and also the conversion by hydrolysis of said nicotinonitriles to the corresponding nicotinamides and subsequent conversion of the latter to the corresponding 3-amino-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones.
Lesher, Opalka and Page U.S. Pat. No. 4,312,875, issued Jan. 26, 1982 from application Ser. No. 204,726, filed Nov. 6, 1980 as a continuation-in-part of U.S. application Ser. No. 135,100, filed Mar. 28, 1980 and now U.S. Pat. No. 4,297,360, issued Oct. 27, 1981, discloses and claims as cardiotonics, 6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones.
(c) Prior Publications
The following publications appeared prior to the filing of the instant application but subsequent to completion of applicants' invention disclosed and claimed herein: Sandoz AG U.K. patent application No. 2,070,606, published Sept. 9, 1981, and corresponding Belgian Pat. No. 887,737, published Sept. 2, 1981, which disclose, inter alia, as cardiotonic agents and claim selected 3-amino-6-R.sub.2 -5-aryl-2(1H)-pyridinones where R.sub.2 is hydrogen or lower-alkyl and aryl is, inter alia, 4-thiazolyl. These compounds are reportedly prepared from the corresponding 1,2-dihydro-2-oxo-6-R.sub.2 -5-arylnicotinamides, in turn, prepared from the corresponding 1,2-dihydro-2-oxo-6-R.sub.2 -5-arylnicotinonitriles, in turn, prepared by reacting cyanoacetamide with 4-dimethylamino-3-aryl-3-buten-2-one.